Chronically stressed individuals are at increasing risk for cardiovascular disease and mortality, and as such, it is imperative to discover behavioral and biological mechanisms through which these effects could be mitigated. Human and mouse studies support the critical role that the telomere/telomerase maintenance system plays in cardiovascular disease and mortality. Telomeres are the protective caps at the ends of chromosomes and telomerase is the enzyme that lengthens telomeres. Chronic stress is related to decreased telomerase levels and shorter telomeres, and thus telomere maintenance may play a critical role in mediating the chronic stress- cardiovascular disease link. On the other hand, exercise, which is consistently linked to improved cardiovascular health, predicts longer telomeres and increased telomerase levels. The interplay among exercise and chronic stress is rarely examined and thus the cardiovascular benefits of exercise to chronically stressed individuals are poorly understood. The current K99/R00 Pathway to Independence Award seeks to build on previous cross-sectional work that demonstrates the potential for exercise to buffer the chronic stress- telomere length association, with the ultimate goal of deepening the understanding and promotion of cardiovascular health. First, the award will provide the opportunity to strengthen my understanding of exercise physiology, measurement and use in interventions, and to complete successful apprenticeships with leading experts in cardiovascular disease, exercise interventions, and cell aging. The proposed training will include brief courses offered through UCSF, UC Berkeley, NIH, CDC, and Johns Hopkins. Second, using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, I will examine the prospective relationships of exercise with cardiovascular functioning in middle-aged adults, and the possible mediating role of telomere length. I will also test the longitudinal associations of maintaining higher levels of physical activity and accumulation of life stress over a 20-year period with CVD risk, and the mediating role telomere length may play in these associations. Finally, I will conduct a three-month randomized controlled aerobic training intervention in caregivers compared to an age-matched wait list control group with the aims of increasing leukocyte telomerase activity, improving exercise capacity and blood pressure, and decreasing psychological distress. The proposed training plan and series of studies will deepen our understanding of the biological mechanisms through which exercise confers cardiovascular benefits, with a primary focus on telomere length and telomerase activity levels as mediators. These findings can provide new understanding of pathways to cardiovascular health that may lead to innovative ways to encourage greater activity in stressed individuals, a public health goal that has been difficult to attain. PUBLIC HEALTH RELEVANCE: Chronic stress is an important predictor of cardiovascular disease and early mortality, and a possible biological mechanism through which this occurs is accelerated immune cell aging. The current series of naturalistic and intervention studies seek to clarify the role that stress and immune cell aging plays in cardiovascular disease in humans, and importantly to test the mitigating role that exercise may have in these relationships.